Comutation of <i>PIK3CA</i> and <i>TP53</i> in Residual Disease After Preoperative Anti-HER2 Therapy in ERBB2 (HER2)-Amplified Early Breast Cancer.

Abstract

To identify proteomic and genomic alterations in residual disease (RD) for human epidermal growth factor receptor 2 (HER2)-positive (HER2+) breast cancer (BC) after preoperative trastuzumab (H), lapatinib (L), or both (H+L) in combination with chemotherapy. Patients with stage II/III HER2+ BC (n = 100) were randomly assigned to preoperative treatment with H versus L 1,250mg versus H+L (L: 750 to 1,000 mg) plus 5-fluorouracil, epirubicin, and cyclophosphamide, followed by weekly paclitaxel. After receiving institutional review board-approved informed consent, targeted next-generation sequencing was performed on 20 patients' formalin-fixed paraffin embedded tumors to characterize genomic alterations across 287 cancer-related genes. Reverse phase protein array (RPPA) analysis was performed on both the baseline biopsy and RD specimens, when available. Two of 20 RD tissues were HER2 negative per next-generation sequencing; one sample had insufficient tissue. Of six pretreatment biopsy specimens, four were comutated with <i>TP53</i> and <i>PIK3CA</i>. Of 17 HER2+ RD, seven specimens (41%) had <i>PIK3CA</i> mutations always comutated with <i>TP53,</i> and four (24%) also had concurrent <i>CDK12</i> amplification. Overall, <i>CDK12</i> amplification was observed in eight of the 17 (47%) HER2+ RD specimens. A total of 12 RD specimens (71%) had <i>TP53</i> mutations. Although prevalence of individual <i>TP53</i> and <i>PIK3CA</i> mutations was only modestly higher than published estimates for those in HER2+ primary BCs (55% and 32% for <i>TP53</i> and <i>PIK3CA</i>, respectively), prevalence of these as comutations appeared higher (41%), compared with less than 10% in several series. On RPPA analysis of the RD tissue with comutations, the strongest Spearman ρ correlations were limited to EGFR and phospho-AKT (ρ, 0.999; <i>P</i> = .019) and phospho-mTOR and phospho-S6 ribosomal protein (ρ, 0.994; <i>P</i> = .048). HER2-amplified RD tissue after preoperative H, L, or H+L plus chemotherapy was enriched for <i>PIK3CA</i> and <i>TP53</i> comutations, and the RD tissue demonstrated activation of EGFR/AKT/mTOR signaling on RPPA.